Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Anesthetic Considerations in Porphyrias Niels F. Jensen, MD* Daniel S. Fiddler, MD** Volker Striepe, MBBCh, DA, FFA(SA)*** *Assistant Professor, Department of Anesthesiology, University of Iowa **Anesthesia Associates of Medford, Medford, Oregon ***Assistant Professor, Department of Anesthesiology, Vanderbilt University Address correspondence to Dr. Jensen, Department of Anesthesiology, University of Iowa College of Medicine, Iowa City, Iowa 52242. (319) 356-2633 No reprints available. 1 Key Words: Complications: porphyria; Acute intermittent porphyria (AIP); ALA dehydratase deficiency porphyria (PLP); Hereditary coproporphyria (HCP); Porphyria cutanea tarda (PCT); Variegate porphyria (VP) 2 Outline I. Introduction II. Pathophysiology III. Classification and Incidence IV. Clinical features: acute attack V. Preoperative evaluation a. Acute abdomen and porphyria b. Known acute porphyria VI. Intraoperative management a. Regional anesthesia b. Induction agents c. Maintenance agents d. Treatment of complications e. Monitoring VII. Postoperative management VIII. Treatment: acute crisis IX. Further investigation X. Summary 3 Introduction Porphyrias present special anesthetic challenges, including preoperative assessment of a patient with acute abdominal pain, intraoperative management of known porphyria, and respiratory and cardiovascular management of acute porphyric crisis. To meet these challenges, a current and thorough understanding of porphyria is essential. Several years have elapsed since there has been a comprehensive review of the spectrum of issues related to porphyria of concern to the anesthesiologist: presentation, pathophysiology, monitoring, and relevant pharmacology. The last significant review of this subject provided a pharmacologic perspective but much relevant anesthetic information was not addressed, such as new methods of detection and the evolving role of hematin and heme arginate in treatment. (1) DNA analysis of suspected porphyric patients promises earlier, definitive diagnosis of the disease and thereby the opportunity for safer anesthetic management. This management may soon include heme arginate, the most stable form of heme, which currently lacks FDA approval but is soon to be tested in clinical trials in the United States. Safe anesthetic management of porphyria demands far more today than an understanding of appropriate pharmacologic therapy. It demands a thorough, current understanding of many other aspects of the disease. Pathophysiology The porphyrias are a group of inherited or acquired enzymatic defects of heme biosynthesis. Each type of porphyria has a characteristic pattern of overproduction and accumulation of heme precursors based upon the location of the dysfunctional enzyme in the heme synthetic pathway (Fig. 1). The rate limiting step in heme synthesis is the condensation of succinyl CoA and glycine to form delta-amino levulinic acid (ALA), (2, 3) catalyzed by the mitochondrial enzyme ALA synthetase. The basal activity of ALA synthetase is substantially lower than that of subsequent enzymes in the synthetic pathway, and therefore changes in ALA synthetase activity are rate limiting, controlling the rate of heme synthesis. Heme, the end product of the synthetic pathway, exerts negative feedback regulation on ALA synthetase activity. (4-6) The specific enzyme deficit in each type of porphyria results in a partial block in heme biosynthesis and lower intramitochondrial heme levels (see Fig. 1). Decreased negative feedback from heme contributes to the elevated “baseline” ALA synthetase activity which is characteristic of the porphyrias. (4-6) The manifestions of the disease are thought to be due to increased ALA synthetase activity, increased porphyrin accumulation in the tissues, or decreased heme production.(4-6) The increased ALA synthetase activity results in elevated levels of heme precursors proximal to the site of the specific enzyme deficiency. These precursors are colorless and nonfluorescent 4 porphyrinogens. Irreversible oxidation of these porphyrinogens causes the formation of porphyrins, which have no known physiologic function but are highly reactive oxidants. The accumulation of porphyrins in the epidermal skin layers leads to cutaneous photosensitivity. (7) Acute porphyria often causes severe neuropathy, the basis for multisystem impairment. Changes in autonomic ganglia, anterior horns of the spinal cord, peripheral nerves, brainstem nuclei, cerebellar axons, schwann cells and myelin sheaths have been demonstrated. (6, 8-12) Neuronal damage and axonal degeneration may be the primary pathologic lesions, with later axonal changes leading to secondary demyelination. (4, 6) Many hypotheses have been proposed to explain the mechanism of porphyric neuropathy. (4, 9) Two of the most plausible attribute the neuronal dysfunction to direct neurotoxicity of ALA [not porphobilinogen (PBG)], or to diminished intraneuronal heme level or both. (4, 6, 11) In addition, there may be a significant relationship between tryptophan metabolites and/or folate deficiency and clinical expression of the disease. (13, 14) Recent reviews provide additional detail. (4, 6, 9) Classification and Incidence The porphyrias may be classified according to three characteristics: 1. The major site of abnormal porphyrin production (hepatic versus erythropoietic) 2. Acute or nonacute presentation 3. Pattern of enzyme deficiency in heme production (Table I) (4) Heme is a component of microsomal and mitochondrial cytochrome systems and is synthesized and utilized in all cells. The two major quantitative sites of heme synthesis are erythropoeitic and hepatic cells where heme is incorporated into hemoglobin and hepatic cytochromes. Erythropoeitic porphyrias cause extreme skin sensitivity but lack neurologic involvement and are not associated with drug precipitated crises. Porphyria cutanea tarda (PCT) is the only hepatic porphyria without neurologic sequelae. PCT is usually associated with hepatic disease but not acute neurologic crisis. Other hepatic porphyrias are associated with abdominal pain, peripheral neuropathy, and mental status changes, with crisis frequently precipitated by "triggering" drugs. Barbiturates are the most frequent "trigger".(9, 15) There is little difference in the neurologic syndrome exhibited during an attack among the four acute hepatic porphyrias. Hereditary coproporphyria (HCP) and variegate porphyria (VP) manifest skin photosensitivity and extreme skin fragility, whereas acute intermittent porphyria (AIP) does not. (4-6) Once diagnosed, AIP is associated with a relatively good prognosis. Symptoms occur in less than one third of genetically susceptible patients but rarely before puberty. Acute attacks 5 are associated with a significant risk of mortality, particularly if the diagnosis is delayed and neurologic involvement progresses. Although autosomal dominant, clinical expression is more common in females. (16) Most patients with HCP are asymptomatic and clinical onset may be associated with intercurrent hepatic disease. Presentation has occurred between the ages of 7 and 75 years. Prognosis is generally good. (17) VP has a prognosis as good as acute intermittent porphyria. Systemic effects are more common in women, while cutaneous manifestations are more common in men. (17) Treatment of known hepatic porphyria consists of prophylaxis and treatment of the acute attack. Factors known to precipitate acute porphyric crisis include fasting/dehydration, infection, psychological stress, physiological hormone variation, excessive alcohol intake, and administration of specific drugs. Many drugs cause porphyric crisis (see Table II). Most do so by decreasing heme levels, thus decreasing negative feedback and thereby increasing ALA synthetase activity. (4-6) Many commonly used drugs trigger porphyric crisis by decreasing heme. (2) Barbiturates induce the cytochrome P450 system; this incorporates more heme into the new cytochromes, thereby decreasing heme levels. Oral contraceptives cause destruction of the heme group in cytochromes, requiring new heme for incorporation into cytochromes. Griseofulvin converts heme into N-methylated derivatives, which further inhibit heme synthesis. Some endogenous steroid hormones are thought to trigger porphyria by increasing the synthesis of new ALA synthetase enzyme. (2) Factors known to decrease synthetase activity include high carbohydrate (glucose) loading, propranolol, and increased negative feedback from heme. (3-6, 18) Propranolol is used during the acute porphyric attack to control hypertension and tachycardia. This drug increases heme synthesis in vitro, which exerts an inhibitory effort upon ALA synthetase activity through negative feedback. (19) The acute porphyrias are associated with hereditary enzyme deficits. (20-24) AIP, HCP, and VP exhibit autosomal dominant transmission with variable expression. The frequency of AIP is estimated to be 1/20,000 in Europe, with a high of 1/10,000 in Northern Sweden. (4, 25) ALA dehydratase deficiency porphyria, also known as plumboporphyria (PLP), has an autosomal dominant pattern. Since PLP has only recently been described, no estimate of prevalence has been established. (26-28) The frequency of HCP is also difficult to estimate since greater than half of affected individuals are asymptomatic (variable expression) and the number of reported cases is small. (4) VP is particularly common in certain 6 population groups, such as white South Africans, where prevalence has been estimated at 1/250-500. (4, 29) Pregnancy may exacerbate or provoke an acute attack. Avoidance of planned pregnancy until a one year latent period has elapsed is recommended. The mortality rate from acute attack among pregnant patients has been reported to be as high as 42%.(30) Clinical Features: Acute Attack Acute attacks only occur in four types of porphyria: AIP, HCP, VP, and PLP. (7) The signs and symptoms of acute porphyric crisis are well-known and quite consistent: severe abdominal pain, vomiting, anxiety, confusion, autonomic instability manifested by hypertension and tachycardia, dehydration, and electrolyte disturbances such as hyponatremia, hypokalemia, and hypocalcemia. (22, 24, 31) (Table III) AIP, HCP, and VP may be clinically indistinguishable during acute attacks. (32) Central to each is neurologic dysfunction (Table III) (9, 29) , with significant impairment of both sympathetic and parasympathetic nervous systems occurring during an acute attack. (33) During remissions function improves, but parasympathetic dysfunction can persist. (33) Tachycardia is often an indicator of disease state progression. (25, 34, 35) As heart rate increases, the patient's condition generally worsens and with clinical improvement tachycardia usually resolves. Most of the clinical features subside within the approximate time course of the acute crises, but residual paresis may persist for years in the absence of further attacks. (34) This paresis, per se, does not have specific implications for the use of neuromuscular relaxants. The use of muscle relaxants in the setting of porphyria is discussed below. Recovery of mental function often lags behind physical recovery, and some patients report anxiety, emotional instability, or other functional disturbances indefinitely. (29) Electrolyte abnormalities occur secondary to dehydration, vomiting, and diarrhea and may entail serious hyponatremia and hypochloremia. (6) Stein et al performed radioisotope studies to measure blood volume in nine AIP patients. (35) All had low blood volumes, ranging from 67% to 97% of normal, despite normal electrolytes in some patients. Though the syndrome of inappropriate secretion of anti-diuretic hormone (siADH) is well described in acute porphyrias, presumably due to hypothalamic involvement, hyponatremia with appropriate ADH levels occurs more often. (34-36) Laboratory diagnosis of porphyric crisis can involve fecal analysis (32) but most frequently involves quantification of urinary porphyrin and porphyrinogen precursors. (37) These can be markedly elevated during an attack, but may return to normal during remission. This normality can create a difficulty in early and accurate diagnosis in high risk groups, such 7 as in patients with a strong family history for porphyria. Many carriers of the trait can thus remain asymptomatic unless exposed to precipitants. One technique known as gene linkage analysis offers a new approach to the diagnosis of acute intermittent porphyria and relies on direct cDNA sequencing. (20, 22) It does not depend on urinalysis but rather on polymorphic markers within the porphobilingen deaminase gene. (21) This permits unequivocal and early detection of carriers. Early and accurate detection of the disease in high risk patients is of obvious benefit to safer anesthetic management of those affected and constitutes a major breakthrough in terms of perioperative anesthetic management. Preoperative Evaluation A. Acute Abdomen and porphyria: The following symptoms should raise suspicion of porphyria in patients with acute abdominal pain: mental status changes (confusion, hysteria), peripheral neuropathy (motor > sensory), dark colored (red to purple) urine, and known family history of porphyria. (38) Of special concern is the parturient with acute abdominal pain. Greater than 50% of pregnant women who have porphyria will experience a crisis during pregnancy or puerperium, (39) probably due to ALA sythetase induction by hormonal changes of pregnancy. If the patient with an acute abdomen, pregnant or not, does not have suggestive symptoms of porphyria, anesthetic drugs and therapies should not be modified. (40) B. Known acute porphyria: In the setting of known acute porphyria, perhaps the most difficult situation is when an acute attack is caused by and is concurrent with a disease process which mandates surgical intervention; i.e. the infection, pyrexia, and anorexia of acute appendicitis inducing ALA synthetase and precipitating crisis. Neurologic evaluation should focus on mental status and peripheral neuropathy. If an acute crisis is suspected, attention to cranial dysfunction and bulbar symptomatology may predict impending respiratory failure. Premedication is important, as psychological stress alone has been reported to precipitate crises. (18, 34, 36) Numerous reports have implicated benzodiazepines, (4, 41, 42) and their use is discussed below. Narcotics are safe in porphyria, with the exception of pentazocine, a partial agonist. Scoplamine and atropine are considered safe. Acceptable nonnarcotic sedative include droperidol, promethazine, chloral hydrate, and diphenhydramine. Intraoperative Management A. Regional anesthesia Acute porphyria is not an absolute contraindication to regional anesthesia but in the setting of peripheral neuropathy detailed preoperative examination and documentation is 8 essential. Potential mental status changes and patient cooperation is especially important in this setting. Bupivacaine is considered safe for regional anesthesia. While some evidence suggests that lidocaine may increase ALA synthetase activity in animal tissue culture cells, no clinical exacerbations have been reported after the administration of ester or amide local anesthetics. (1, 43) Procaine decreases ALA synthase activity in the rat liver experimental model. (43) Regional anesthesia should probably be avoided in the setting of acute porphyric crisis. Associated neuropathy may be rapid in onset, clouding the differentiation between regional anesthetic onset and progressive porphyric neuropathy. In addition, mental status changes often make porphyric patients uncooperative. Finally, hypovolemia and a labile autonomic response, characteristic of acute porphyric crisis, increase the risk of hemodynamic instability in the setting of a sympathectomy. In fact, however, there are no studies specific to this issue--probably secondary to the ethical and medicolegal issues surrounding the institution of regional anesthesia while acute neurologic deterioration is occuring. B. Induction of anesthesia Thiopental has accounted for the majority of drug-precipitated attacks(15, 35) but the multifactorial nature of porphyric crisis makes interpretation of isolated cases difficult. (18) Since dehydration, infection, fever, and endogonous steroid hormones themselves induce ALA synthetase, virtually any drug administered to a patient entering a porphyric crisis implicates that drug as a "trigger".(18) Interestingly, even a known trigger may not induce an attack. (5, 44) For example, Ward reviewed 36 cases of barbiturate induction of general anesthesia in patients with porphyria. None had a postoperative porphyric crisis. (40) In another study, thiopental was administered to 27 patients with an acute porphyria but not in crisis. (5) None of these patients developed an attack postoperatively. Of 10 patients who were in acute crisis prior to anesthetic induction with thiopental, however, seven had worsening of porphyric symptoms. (5) These results suggest that administration of porphyrinogenic drugs does not, by itself, determine if an attack will occur. Administration of such drugs is therefore probably only one factor which may precipitate crisis. Therefore, although thiopental will not always precipitate crisis, barbiturates are contraindicated in known porphyric patients. (9) Benzodiazepines vary in their porphyrinogenic potential. Diazepam has been implicated as a "trigger" as have chlordiazepoxide, flunitrazepam and nitrazepam. (1, 6) However, diazepam has been safely used during porphyric crises. (41) Midazolam has been used safely for induction of anesthesia in patients with confirmed VP, as has (45) lorazepam. (45) 9 Etomidate is porphyrinogenic in animal models. (46) One case has been reported of its use for induction in a latent porphyria patient with an uneventful clinical course , but at least one human porphyric crises has been reported after its use. (47) Ketamine has been implicated as triggering porphyric crisis. (18) Laboratory investigation of tissue culture results are controversial, as ketamine appears to be porphyrinogenic at higher concentrations, but not at clinical levels. (46, 48-50) The validity of extrapolating such in vivo or in vitro animal studies to the clinical human setting is questionable. Many consider ketamine to be safe in porphyrias. (18, 51, 52) Propofol has been suggested as an alternative drug to induce anesthesia. Many porphyric patients have received propofol with no clinical evidence of resultant acute crisis,(46, 53-62) ALA synthetase is not induced in animal models. (63) (64) A prospective clinical trial of 13 VP subjects showed no evidence of porphyrinogenicity when propofol was used for the induction of anesthesia. (7) A single recent case report of a patient with VP noted modest elevations of urinary porphyrins after a propofol infusion. (33) However, as was pointed out by Harrison et al this increase occured after the third consecutive anesthetic and was not accompanied by any symptoms. (1, 7) Propofol is therefore considered "probably safe" although careful monitoring for porphyrinogenesis after anesthesia is suggested. (1) B. Maintenance of anesthesia Volatile anesthetics are generally considered safe in porphyric patients. Reports of a possible association of halothane with crises contradict both experimental and clinical experience. (3, 18) Neither isoflurane nor enflurane exacerbate porphyric crisis in humans. (3, 18) However, enflurane has been classified as porphyrinogenic based on animal data. (43, 65) Nitrous oxide and opioids are considered safe. (9) d-Tubocurarine and succinylcholine have been used extensively and are safe. (9) Whether there is any degree of hyperkalemic response to succinylcholine is not known, but, again, succinylcholine has been used extensively and is considered safe in porphyrics. Other muscle relaxants reported as safe include vecuronium and atracurium. (1, 66) It is interesting to note that some steroids are considered unsafe in porphyria. Vecuronium and pancuronium share a steroid structure , but only the latter has been incriminated as unsafe based on data obtained from animals. (1, 25, 41) Long-term experience and definitive data are lacking. C. Treatment of complications Hypertension and tachycardia are common features of an acute attack and beta adrenergic blockers are the most appropriate therapy. (38, 67-69) Propranolol decreases ALA synthetase activity and increases intracellular heme levels in tissue culture. (19) It is not known definitely if these effects occur with other beta adrenergic blockers, such as labetalol or 10 esmolol, but atenolol, a selective β-1 adrenoceptor blocker, is safe. (6) Alpha-methyldopa is contraindicated--with both clinical and laboratory reports implicating it in porphyric crisis. (9) Hydralazine is also associated with laboratory evidence of porphyinogenicity. (9) Since 20% of patients in porphyric crisis develop generalized convulsions, safe anticonvulsant therapy is necessary. Standard anticonvulsants including dilantin, barbiturates, and diazepam are safe. (41, 70 ) Bromides are effective oral treatment for chronic management but are not available for acute seizure management. Diazepam has been recommended for acute seizures despite reports of porphyria crises after its administration. (3 , 4, 41, 71) Magnesium sulfate is effective in hypomagnesemic porphyria patients. (72) D. Monitoring Hypovolemia and autonomic neuropathy with labile hypertension suggests the value of invasive blood pressure monitoring during an acute crisis. Central venous pressure monitoring may be warranted in the setting of ischemic cardiac disease, clinical findings consistent with heart failure, and procedures where excessive blood loss or fluid shifts are anticipated. There is no documentation of a primary cardiomyopathy associated with this disease. The cardiovascular manifestations seen are secondary to its autonomic nervous system manifestations aggravated by electrolyte disturbances described above. These may have greater implications in the face of co-existing cardiac disease. Postoperative Management Monitoring for the potential onset of porphyric crisis should be continued for up to five days, since onset may be delayed. The onset of crisis may be heralded by either neurologic signs or autonomic nervous system stimulation. (16) In such patients, appropriate cardiovascular monitoring may include electrocardiography, as well as a pulmonary artery catheter, to evaluate cardiac function and aid in the diagnosis and treatment of cardiac failure. Cardiovascular monitoring in the setting of an acute attack should be continued postoperatively--the extent determined by clinical circumstances. The incidence of postoperative cardiac failure following acute porphyric attack is unknown. The institution of invasive monitoring of volume status should be guided by the type, duration, and extent of surgery and blood loss and the clinical status of the patient postoperatively. Neurologic status should be assessed frequently postoperatively. If anti-emetic therapy is indicated, metoclopramide should probably be avoided, but promethazine, droperidol, or chlorpramazine are acceptable (see below). (6) Treatment: acute crisis 11 Management of acute porphyric crisis involves specific attempts to reverse factors which increase ALA synthetase activity, withdrawal of offending drugs, treatment of symptoms with appropriate medications, and appropriate patient monitoring. Primary treatment, directed at reversing the disease process includes hydration, electrolyte monitoring, administration of glucose (20g/hr), propranolol (which may decrease enzyme activity as well as control tachycardia), treatment of underlying infection and heme--which directly increases negative feedback to ALA synthetase. (4-6) Hematin, the preparation used most often in the treatment of porphyria, is standard therapy, but probably not the best. Hematin has produced dramatic clinical improvement, with marked decreases in urinary amino-levulinic acid and prophobilinogen excretion. (67) Associated problems with hematin, however, are significant and include renal failure, thrombophlebitis, and dose related coagulopathy. (11, 73, 74) These negative side effects are largely secondary to the inherent instability of the compound in the infusate. The shelf-life of hematin is only about three months. These problems and this instability has led to the introduction of another heme compound, heme arginate. Heme arginate is more stable in solution, has a shelf-life of approximately two years, and does not to the share the undesirable side effects profile of hematin. (75) The response to heme therapy usually occurs within 2-4 days after the start of infusion. Hematin suppresses endogenous heme synthesis and decreases significantly the excretion of ALA and PBG. The only commercial preparation in the United States is Panhematin (Abbott Laboratories, Chicago, IL) at a dose 3-4 mg/kg/day. (73) Parenthetically, it is interesting to note that this was the first drug approved through the Orphan Drug Act. Up to 48 hours of initial treatment without hematin has been recommended by some, withholding its use for refractory or rapidly progressing cases. (76) Recent information however, suggests that the early administration of heme arginate shortens hospitalization and improves outcome. (75) At this time however, heme arginate, the most stable form of the compound, lacks FDA approval and is not available except for research purposes in the United States. Clinical trials are scheduled to begin at the University of Texas Medical Branch at Galveston in the future. Cimetidine may have a role in the treatment of acute intermittent porphyria by inhibiting heme oxidase activity, decreasing heme consumption, and inhibiting ALA synthetase through a negative feedback mechanism. (77) This apparent efficacy led to the supposition that cimetidine may be useful as a prophylactic agent, stabilizing and prolonging periods of remission. Initial laboratory and animal experiments were positive, but human studies have not been confirmatory. While cimetidine does not worsen the clinical course and 12 can be safely used as an H2 antagonist in patients with AIP, it does not appear to be effective prophylactic therapy. (78) Pain associated with an acute attack may require opioid therapy. Nausea and vomiting should be treated with promazine, chlorpromazine, or prochloroperazine, rather than metaclopramide, which is porphyrinogenic. (6) Should bulbar symptoms appear, frequent scrutiny for respiratory failure should be undertaken. Arterial blood gas analysis and serial FVC measurements are often important adjuncts. In patients with a history of coronary artery disease, tachycardia and hypertension characteristic of the acute crisis increase myocardial oxygen demand and should be avoided. Mortality in porphyric crises is about 10% with current treatment regimens and is primarily due to two factors: underlying infectious processes and respiratory failure secondary to depression of central respiratory drive or respiratory muscle paralysis. (4) Cardiac arrest has been reported in severely affected patients with flaccid quadriplegia, coma, and bulbar symptoms. (18) The presence of severe dysrhythmias may precede refractory cardiac arrest. (12, 35) Further Investigation Large clinical studies on the use of ketamine, proprofol, etomidate, and volatile anesthetics are needed. Only anecdotal clinical reports attest to the safety of these anesthetics. Neither laboratory nor clinical investigation of the use of atracurium or vecuronium in porphyria is available. The lack of significant hemodynamic alterations with these drugs makes their availability particularly desirable in this group of patients. Summary Four hereditary types of porphyria are now classified as acute porphyrias. Enzymatic defects result in accumulation of porphyrin precursors (usually ALA and PGB). The quantity of these precursors may be normal or slightly elevated in latent periods but increase to toxic levels during a porphyric crisis. Iatrogenic induction of ALA synthetase by administration of certain triggers (classically barbiturates) is only one of several factors which contribute to porphyric crisis. Signs and symptoms of acute porphyric attack consist primarily of neurologic dysfunction, which occurs secondary to neurotoxicity of ALA or diminished intraneuronal heme levels. Appropriate anesthetic management of porphyria requires a knowledge of the type of porphyria (acute vs. non-acute), assessment of latent versus active (crisis) phase, awareness of clinical features of porphyric attack, and knowledge of safe pharmacologic intervention. 13 1. Harrison GG, Meissner PN, Hift RJ. Anaesthesia for the porphyric patient. Anaesthesia 1993; 48: 417-421. 2. Elder GH, Path FRC. Enzymatic defects in porphyria: An overview. Seminars in Liver Disease 1982; 2: 87-99. 3. Moore MR, Disler PB. Drug induction of the acute porphyrias. Adv Drug React Ac Pois Rev 1983; 2: 149-89. 4. Moore MR, McColl KEL, Remington C, Goldberg A. Disorders of porphyrin metabolism. In: ed. New York: Plenum Medical Book Company, 1987; 5. Mustajoki P, Heinonen J. General anesthesia in "inducible" porphyrias. Anesthesiology 1980; 53: 15-20. 6. Yeung Laiwah AC, McColl KEL. Management of attacks of acute porphyria. Drugs 1987; 34: 604-16. 7. Meissner PN, Jarrison GG, Hift RJ. Propofol as an I.V. anaesthetic induction agent in variegate porphyria. Br J Anaesth 1991; 66: 60-65. 8. Becker DM, Kramer S. The neurological manifestations of porphyria: A review. Medicine 1977; 56: 411-423. 9. Bonkowsky HL, Schady W. Neurologic manifestations of acute porphyria. Semin Liver Dis 1982; 2: 108-24. 10. Cavanagh JB, Ridley AR. The nature of the neuropathy complicating acute intermittent porphyria. The Lancet 1967; November 11: 1023-1023. 11. Pierach CA, Watson CJ. Treatment of acute hepatic porphyria. Lancet 1978; 1: 1361. 12. Yeung Laiwah AC. Autonomic neuropathy in acute intermittent porphyria. J Neurol Neurosurg Psychiatry 1985; 48: 1025-30. 13. Puy H, Deyback J, Baudry P, et al. Decreased nocturnal plasma melatonin levels in patients with recurrent acute intermittent porphyria attacks. Life Sciences 1993; 53: 621-627. 14. DiMario Jr. FJ, Quinn JJ, Zalneraitis EL, et al. Folate deficiency and acute intermittent porphyria in a 12-year-old boy. Neurology 1993; 43: 1438-1439. 15. Eales L. Porphyria and the dangerous life-threatening drugs. SA Medical Journal 1979; November 24: 914-917. 16. Goldbery A, Moore MR, McColl KE, Brody, MJ. Porphyrin metabolism and the porphyrias. In: Oxford Textbook of Medicine, 2nd edition, vol. 1, Weatherall DJ, Ledingham JGG, Warrell DA ed. Oxford Medical Publications, Oxford, 1987: 9.136-9.144. 17. Meyer, UA. Porphyria. In: Harrison's Principles of Internal Medicine, Wilson, JD, ed. McGraw Hill, New York, 1991: 1829-1834. 18. Disler PB, Eales L. The acute attack of porphyria. S Afr Med J 1982; 61: 82-4. 14 19. Epstein O, Schoenfeld N, Greenblat Y, et al. The influence of propranolol on the concentration of heme and on the activity of d-aminolevulinate synthase in monolayers of chick embryo liver cells. Biochemical Pharmacology 1982; 31: 485-489. 20. Mgone CS, Lanyon WG, Moore MR, Connor JM. Detection of seven point mutations in the porphobilinogen deaminase gene in patients with acute intermittent porphyria, by direct sequencing of in vitro amplified cDNA. Human Genetics 1992; 90: 12-16. 21. Schreiber WE, Jamani A, Ritchie B. Detection of a t/c polymorphism in the porphobilinogen deaminase gene by polymerase chain reaction amplification of specific alleles. Clinical Chemistry 1992; 38: 2153-2155. 22. Bjersing L, Andersson C, Lithner F. Easy detection of mutations in acute intermittent porphyria and hepatocellular carcinoma on paraffin-embedded tissue. Journal of Internal Medicine 1993; 234: 339-340. 23. Llewellyn DH, Whatley S, Elder GH. Acute intermittent porphyria caused by an arginine to histidine substitution (R26H) in the cofactor-binding cleft of porphobilinogen deaminase. Human Molecular Genetics 1993; 2: 1315-1316. 24. Kauppinen R, Peltonen L, Pihlaja H, Mustajoki P. CRIM-Positive mutations of acute intermittent porphyria in Finland. Human Mutation 1992; 1: 392-396. 25. Tschudy DP, Valsamis M, Magnussen CR. Acute intermittent porphyria: clinical and selected research aspects. Ann Int Med 1975; 83: 851-64. 26. Bird TD, Hamernyik P, Nutter JY, Labbe TR. Inherited deficiency of delta-aminolevulinic acid dehydratase. Am J Hum Genet 1979; 31: 662-8. 27. Doss M, Schneider J, VonTiepermann R, Brandt A. New type of acute porphyria with porphobilinogen synthase (d-Aminolevulinic acid dehydratase) defect in the homozygous state. Clin Biochem 1982; 15: 52-55. 28. Labbe RF, Bird TJ. More on identifying inherited deficiency of porphobilinogen synthase. Clin Chem 1985; 31: 162. 29. Taddeini L, Watson CJ. The clinical porphyrias. Semin Hematol 1968; 5: 335-69. 30. Kanaan C, Veille JC, Lakin M. Pregnancy and acute intermittent porphyria. Obstet Gynecol Surv 1989; 44: 244-9. 31. Hift RJ, Meissner PN, Meissner DM. Porphyria: A guide for people with porphyria and their doctors. MRC/UCT Liver Research Centre 1991; 1-45. 32. Minder EI. Coproporphyrin isomers in acute-intermittent porphyria. Scand J Clin Lab Invest 1993; 53: 87-90. 33. Weir PM, Hodkinson BP. Is propofol a safe agent in porphyria? Anaesthesia 1988; 43: 102223. 34. Eales L, Linder GC. Porphyria - the acute attack: analysis of 80 cases. S Afr Med J 1962; 284-92. 15 35. Stein JA, Tschudy DP. Acute intermittnet porphyria: a clinical and biochemical study of 46 patients. Medicine 1970; 49: 1-16. 36. Eales L, Dowdle EB. Electrolyte abnormalities in porphyria. Lancet 1969; 1: 51. 37. Hernandez A, Sepulveda P, Fernandez-Cuartero B, DeSalamanca RE. Urinary porphyrinogens in normal subjects and in patients with porphyria cutanea tarda and acute intermittent porphyria. Horm. metab. Res. 1993; 25: 454-455. 38. Srugo I, Said E, Korman S, Jaffe M. Acute intermittent porphyria - an unusual case of "surgical abdomen". Eur J Pediatr 1987; 146: 305-8. 39. Brodie MJ, Moore MR, Thompson GG, et al. Pregnancy and the acute porphyrias. B J Ob Gyn 1977; 84: 726-731. 40. Ward RJ. Porphyria and its relation to anesthesia. Anesthesiology 1965; 26: 212-5. 41. Moore MR. International review of drugs in acute porphyrias - 1980. Int J Biochem 1980; 12: 1089-97. 42. Stone DR, Munson ES. Anaesthetics and porphyria. Br J Anaesth 1979; 51: 808. 43. Parikh RK, Moore MR. Effect of certain anesthetic agents on the activity of rat hepatic delta -aminolaevulinate synthase. Br J Anaesth 1978; 50: 1099. 44. Slavin SA, Christoforides C. Thiopental administration in acute intermittent porphyria without adverse effect. Anesthesiology 1976; 44: 77-9. 45. Freedman M, Ingram HJ, Smuts JHL. Midazolam for the induction of anesthesia in patients with porphyria. SAMJ 1985; 68: 212. 46. Harrison GG, Moore MR, Meissner PN. Porphyrinogenicity of etomidate and ketamine as continuous infusions. Br J Anaesth 1985; 57: 420-423. 47. Famewo CE. Induction of anesthesia with etomidate in a patient with acute intermittent porphyria. Can Anaesth Soc J 1985; 32: 171-3. 48. Kostrzewska E, Gregor A, Lipinska D. Ketamine in acute intermittent porphyria dangerous or safe? Anesthesiology 1979; 51: 184. 49. Rizk SF. Ketamine is safe in acute intermittent porphyria. Anesthesiology 1979; 51: 184. 50. Rizk SF, Jacobson JH, Silvay G. Ketamine as an induction agent for acute intermittent porphyria. Anesthesiology 1977; 46: 305-6. 51. Capouet V, Dernovoi B, Azagra JS. Induction of anaesthesia with ketamine during an acute crisis of hereditary coproporphyria. Can J Anaesth 1987; 34: 388-390. 52. Silvay G, Miller R, Tausk C. Safety of ketamine in patients with acute intermittent porphyria. Acta Anaesth Scand 1979; 23: 329-30. 53. Hodkinson B. Porphyria and propofol. Anaesthesia 1989; 89: 613. 54. Parr MJA, Hayden Smith J. Propofol, porphyria and epilepsy. Anaesthesia 1990; 45: 594. 16 55. Meissner PN, Hift RJ, G HG. Porphyria and propofol. Anaesthesia 1989; 44: 612-613. 56. Richard T, Haberer JP. Use of propofol (Diprivan) in a patient with intermittent porphyria. Ann Fr Anesth Reanim 1988; 7: 772. 57. McLoughlin C. Use of propofol in a patient with porphyria. Br J Anaesth 1989; 62: 114. 58. Cooper R. Anaesthesia for porphyria using propofol. Anaesthesia 1988; 43: 611. 59. Mitterschiffthaler G, Theiner A, Hetzel H. Safe use of propofol in a patient with acute intermittent porphyria. Br J Anaesth 1988; 60: 109-11. 60. Malthe R, Fouilloux P. Using propofol in a female patient with acute intermittent porphyria. Ann Fr Anesth Reanim 1989; 8: 297. 61. Montange F, Thomas B, Truffa Bachi J. Use of propofol in a patinet suffering from acute intermittent porphyria. Ann Fr Anesth Reanim 1989; 8: 62. Hughes PJ. Propofol in acute porphyrias. Anaesthesia 1990; 45: 415-16. 63. Parikh RK, Moore MR. A comparison of the porphyrinogenicity of di-isopropylphenol (propofol) and phenobarbitone. Biochem Soc Trans 1986; 14: 726-27. 64. Bohrer H, Schmidt H, Augenstein T, et al. Porphyrinogenicity and metabolic effects of propofol in am AIA-primed rat model. European Journal of Anaesthesiology 1991; 8: 486. 65. Buzaleh A, De Salamanca R, Del C Battle A. Porphyrinogenic properties of the anesthetic enflurane. Gen Pharmac 1992; 23: 665-669. 66. Bleckenhorst GH, Cook ES, Eales L. Drug safety in porphyria. Lancet 1980; 1: 1366-1367. 67. Brezis M, Ghanem J, Weiler-Ravell D, et al. Hematin and propranolol in acute intermittent porphyria: full recovery from quadriplegic coma and respiratory failure. Eur Neurol 1979; 18: 289-94. 68. Douer D, Weinberger A, Pinkhas J, Atsmon A. Treatment of acute intermittent porphyria with large doses of propranolol. JAMA 1978; 240: 766-768. 69. Menewat AS, Kochar DK, Panwar RB, Joshi CK. Propranolol in acute intermittent porphyria. Postgrad Med J 1979; 55: 546-7. 70. Magnussen CR, Doherty JM, Hess RA, Tschudy DP. Grand mal seizures and acute intermittent porphyria - the problem of differential diagnosis and treatment. Neurology 1975; 25: 1121-5. 71. Moore MR, McColl KEL, Goldberg A. Drugs and the acute porphyrias. Trends In Pharmacol Sci 1981; 2: 330-4. 72. Taylor RL, Bonkowsky HL. Magnesium sulfate for AIP seizures. Neurology 1981; 31: 13711372. 73. Bissel DM. Treatment of acute hepatic porphyria with hematin. J Hepatol 1988; 6: 1-7. 17 74. Morris DL, Dudley MD, Pearson RD. Coagulopathy associated with hematin treatment for acute intermittent porphyria. Ann Int Med 1981; 95: 700-1. 75. Mustajoki P, Nordmann Y. Early administration of heme arginate for acute porphyric attacks. Arch Intern Med 1993; 153: 2004-2008. 76. Mustajoki P. Prevention and treatment of acute porphyric attacks. Ann Clin Res 1985; 17: 289-91. 77. Baccino E, Wah LSHLC, Bressollette L, Mottier D. Cimetidine in the treatment of acute intermittent porphyria. JAMA 1989; 262: 3000. 78. Siepman M, Stolzel U, Sieg I, et al. Cimetidin in der behandlung der akuten intermittierenden porphyrie. Zeitschrift Fur Gastroenterologie 1993; 31: 246-249. 18 TABLE I. Classification of Porphyrias HEPATIC Hepatic Acute Porphyrias Acute Intermittent Porphyria (AIP) Hereditary Coproporphyria (HCP) Variegate Porphyria (VP) ALA Dehydratase Deficiency Porphyria (Plumboporphyria) (PLP) Hepatic Nonacute Porphyrias Porphyria Cutanea Tarda (PCT) 1. Familial 2. Acquired ERYTHROPOIETIC Erythropoietic Porphyria Uroporphyria Protoporphyria Moore MR, McColl KEL, Remington C, Goldberg A: Disorders of porphyrin metabolism. New York: Plenum Medical Book Company, 1987. 19 Table II. Porphyria and Anesthetic Drugs Group Intravenous agents Safe-likely safe Unsafe-likely unsafe Unclear Midazolam Lorazepam Propofol Barbiturates Etomidate Chlordiazepoxide Flunitrazepam Nitrazepam Diazepam Ketamine Nitrous oxide Enflurane Isoflurane Halothane* Inhalation agents NM Blockers Succinylcholine Vecuronium d-Tubocurarine Pancuronium Atracurium Premedicants Scopolamine Atropine Droperidol Promethazine Chloral hydrate Diphenhydramine Cimetidine Narcotics Morphine Fentanyl Pentazosine Sufentanil Anticholinesterases Neostigmine Local anesthetics Bupivacaine Procaine Lidocaine Cardiovascular Atenolol Labetolol Guanethadine Reserpine Phentolamine Alpha methyl Dopa Hydralazine Phenoxybenzamine Glucose loading Anticonvulsants Oral contraceptive Griseofulvin Endogenous steroids Other Modified from Harrison, G.G., et. al. *Despite lack of definitive evidence of its safety, halothane is still recommended as the inhalational agent of choice. 20 Table III. Features of the acute porphyric attack Nervous system dysfunction Approx % Involvement Notes Autonomic Neuropathy Abdominal Pain 95 Vomiting 46 Tachycardia 80 Hypertension 36 Postural Hypotension 21 Peripheral Neuropathy 60 C. Paresis to paralysis of muscle groups or extremities Flaccid quadriplegia Respiratory paralysis Bulbar Involement 30 Vagal-Cranial N. Dysphagia Dysphonia Respiratory dysfunction Hypothalmic Involvement siADH(syn. inappropriate 12 secretion ADH) Pyrexia Cerebral Involvement- 9 55 B. Mental status changes Anxiety, confusion, hysteria, depression, psychosis Seizures 20 Coma 10 21 Laboratory Dark urine 74 Hypochloremia 50 Hyponatremia 41 Hypokalemia 29 siADH 12 Leukocytosis 11 Hypomagnesemia 9 B. B. A. B. All data from Stein and Tschudy(35) except as noted Percentages taken from Eales and Linder(34) due to unclear or unavailable data from Stein. C. Other reviews have reported values up to 55%. Modified from Taddeini and Watson(29) 22 PORPHYRIA TYPE Plumboporphyria ———— (PLP) Acute Intermittent —Porphyria (AIP) HEME BIOSYNTHESIS ENZYMES Glycine + Succinyl CoA ↓ ALA Synthase & Aminolevulinic Acid (ALA) ↓ ALA Dehydratase Porphobilinogen (PBG) ↓ Hydroxymethylbilane ↓ Uroporphyrinogen ↓ Hereditary Coproporphyria —— (HCP) PBG Deaminase Uro'Gen Cosynthase → Uroporphyrin Uro'Gen decarboxylase Coproporphyrinogen → Coproporphyrin ↓ Copro'Gen Oxidase Protoporphyrinogen ↓ Proto'gen Oxidase Variegate ———— Porphyria (VP) Protoporphyrin ↓ Ferrochelatase + Iron HEME + Globin ← → + Apoprotein ↓ ↓ Hemoglobin Other respiratory pigments Figure 1. Enzymatic defects in the acute porphyrias. The porphyrias are a group of inherited or acquired enzymatic defects of heme biosynthesis. Each type of porphyria has a characteristic pattern of overproduction and accumulation of heme precursors based upon the location of the dysfunctional enzyme in the heme synthetic pathway. Modified from Moore MR, McColl KEL, Remington C, Goldberg A. Disorders of Porphyrin Metabolism. (4) 23